Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system affecting nearly one million individuals in the United States. The disease is characterized by acute and chronic inflammation, myelin loss; oligodendrocyte, neuronal and axonal pathology; and progressive neurological dysfunction. A number of breakthrough translational discoveries, and especially the highly beneficial effects of B cell depleting drugs, have set the stage for a growing, yet still imperfect, therapeutic pipeline. Research will fall short of its potential to improve patient outcomes until the trigger(s) of disease onset and modifiers of progression are identified. Central to this project is the hypothesis that B cells presenting in the cerebrospinal fluid (CSF) and peripheral blood during early MS play key roles in triggering MS and in mediating ongoing progressive disease activity. We propose to interrogate unique patient cohorts, including an incident cohort, with novel enabling technologies to identify triggers of MS and modifiers of the clinical course. Well characterized clinical populations, high-field serial magnetic resonance imaging (MRI), genetic information organized as functional operational networks, and a focus on B cell biology are the central elements of this initiative. A primary goal will be to characterize the molecular diversity of B cells and their receptors at various stages of disease to identify pathogenic populations and their antigenic targets. A multi-layered experimental strategy includes single cell B cell transcriptomics, together with comprehensive phage-displayed synthetic human, viral and microbial peptidomes for the screening of antibody fingerprints against external drivers in the serum, CSF, and recombinant antibody libraries. The integrative analysis will contextualize the data using clinical, MRI and genetic determinants, striving to apply rigorous statistical principles, including independent replication.